Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix–Directed Spheroid Formation

Kasagi, Yuta; Harada, Yuka; Morodomi, Yosuke; Iwai, Toshiki; Saito, Satoru; Yoshida, Kumi; Oki, Eiji; Saeki, Hiroshi; Ohgaki, Kippei; Shimada, Masahiko; Onimaru, Manabu; Maehara, Yoshihiko; Yonemitsu, Yoshikazu

doi:10.1158/0008-5472.can-15-1563

Cited by 30 publications

(22 citation statements)

References 28 publications

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“…We also demonstrated that EMT, a critical cellular process to cancer metastasis, is induced by stromal IL-33. SP1 is a key regulator in mediating peritoneal cancer dissemination and niche-directed metastasis [47]. CAFs-derived IL-33 increases SP1 expression in GC cells, which can be attenuated by the ERK1/2 inhibitor U0126; SP1 upregulates ZEB2 expression by binding its promoter, and the inhibition of SP1 is sufficient to prevent ZEB2 expression and EMT.…”

Section: Discussionmentioning

confidence: 99%

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

et al. 2019

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Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.

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Section: Discussionmentioning

confidence: 99%

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

et al. 2019

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“…The expression of CXCR4 and CXCR7 and their ligand CXCL12 has been shown to be elevated in many types of cancer, such as breast cancer, gastric cancer, pancreatic cancer, ovarian carcinoma, cervical carcinoma and oral squamous cell carcinoma . Kasagi et al . previously showed the homing efficiency of CT26 cells to the region highly expressing CXCL12, a chemokine for CXCR4, in a mouse peritoneal dissemination model.…”

Section: Discussionmentioning

confidence: 99%

Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph‐node‐positive lung cancer patients

et al. 2017

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The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site‐specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph‐node‐positive non‐small‐cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1‐2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1‐2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (P = .025 and .033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (P = .040). There was significant difference in OS between 2 groups according to expressions of CXCR4 in PS and CXCL12 in MLN (P = .0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95% CI 1.08‐3.04, P = .023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56% vs 25%, respectively, P < .0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph‐node‐positive NSCLC patients.

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“…23, 24, 25 Moreover, inhibition or knock down of CXCR4 resulted in reduced peritoneal dissemination in mouse models of ovarian cancer. 23, 26, 27 Similarly, overexpression of another chemokine receptor, XCR1, in human ovarian cancer cells leads to increased peritoneal dissemination following intraperitoneal injection of tumor cells into nude mice. 28 The CX3CR1 chemokine receptor mediates adhesion of ovarian cancer cell to the mesothelial surface via membrane-bound chemokine CX3CL1.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients

et al. 2017

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Intraabdominal tumor dissemination is a major hallmark of epithelial ovarian cancer (EOC), but the underlying mechanisms have not been fully elucidated. The CXCR3 chemokine receptor supports migration of tumor cells to metastatic sites, but its role in ovarian cancer metastasis is largely unknown. Herein, we first screened two independent cohorts of high-grade serous ovarian cancers (HGSCs, discovery set n=60, validation set n=117) and 102 metastatic lesions for CXCR3 expression. In primary tumors, CXCR3 was particularly overexpressed by tumor cells at the invasive front. In intraabdominal metastases, tumor cells revealed a strong CXCR3 expression regardless of its expression in the corresponding primary tumor, suggesting a selection of CXCR3-overexpressing cancer cells into peritoneal niches. In support of this, CXCR3 mediated the migration of tumor cell lines OVCAR3 and SKOV3 toward malignant ascites, which was inhibited by a monoclonal anti-CXCR3 antibody in vitro. These results were prospectively validated in ascites-derived tumor cells from EOC patients ex vivo (n=9). Moreover, tumor cell-associated overexpression of CXCR3 in advanced ovarian cancer patients was associated with a reduced progression-free survival (PFS) and overall survival (OS), which remained independent of optimal debulking, age, FIGO stage and lymph node involvement (PFS: hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.30–3.45, P=0.003; OS: HR 2.36, 95% CI 1.50–3.71, P<0.001). These results in ovarian cancer patients identify CXCR3 as a potential new target to confine peritoneal spread in ovarian cancer after primary cytoreductive surgery.

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Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix–Directed Spheroid Formation

Cited by 30 publications

References 28 publications

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis

Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph‐node‐positive lung cancer patients

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients

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